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If you knew you or your loved one had an 85% lifetime risk of breast cancer—a risk > 6 times higher than for most women—what would you do?

Historically, there have been multiple instances of major discoveries that revolutionized our understanding of biology: foundational discoveries like that DNA (and not protein) is the genetic material of inheritance (Hershey-Chase experiments, 1952), and that the genetic code consists of 4 bases (adenine [A], cytosine [C], thymine [T], and guanine [G]) that code for 20 different amino acids (George Gamow and others up till 1961). Indeed, it is now possible to decode an entire human genome in just a few days. The real challenge however, is to be able to understand how this code can be used to promote health and prevent disease.

There’s nothing more personal than your DNA

DNA can be envisioned as our body’s encyclopedia, consisting of ~25,000 tomes, known as genes. The 4-letter alphabet of our DNA (A, T, C, and G) forms “words”, by encoding for proteins that have different functions. When an error happens, the meaning of the encoded “word” changes, often leading to dysfunctional proteins and consequent disease (See the figure below). Errors in the genetic code are known as mutations. When mutations can be passed on to progeny, they are referred to as germline mutations.

Mutations come in different types and result in different outcomes. More serious errors result in significant changes in the meaning of the encoded genetic message.

Mutations come in different types and result in different outcomes. More serious errors result in significant changes in the meaning of the encoded genetic message.

Genetic knowledge is power

You may have heard of actress and humanitarian Angelina Jolie’s preventive double mastectomy surgery in March 2013, and oophorectomy in May 2015 (first removing breasts, then ovaries). Her decision to perform both procedures came from discovering that she has a BRCA1 genetic mutation (a typographical error in her DNA) that put her at significantly higher risk of developing breast and ovarian cancers.

In fact, diseases due to genetic predispositions are more common than we think. In the United States, genetics is the second Relatedly, according to the Online Mendelian Inheritance in Man database, there are 4,653 genes out of an estimated 24,000 (~19%) currently known to be associated with disease. Of all genetic disorders, knowledge regarding how errors in the genetic code cause cancer is amongst the most studied. Such inherited genetic mutations contribute to 5-10% of all cancers. Although this percentage might seem small, this in fact translates to hundreds of thousands of individuals. Moreover, in contrast to cancers arising randomly in the general population, individuals born with cancer-causing mutations tend to have cancer at a much younger age, have more aggressive disease, have cancer in both sides of paired organs (for example both breasts or kidneys), often are affected by cancers in different organs during their lifetimes (for example breast and thyroid), and often have other family members with cancer.

What does “genetic knowledge is power” mean in practical terms?

Based on decades of research, some genes such as BRCA1 are well established to increase an individual’s risk for cancer when the gene is mutated. Therefore, once such mutations are found through simple genetic testing, these individuals are subjected to more intense screening (for example annual mammograms starting at age 30 instead of 50), leading to early detection and cure. In the case of Jolie, there was the option of preemptively striking even before the cancer formed. And because these genetic errors are inherited, identifying such mutations can also help the whole family.

Identifying individuals at genetic risk for cancer.

The ultimate goal is to take such gene discoveries from the bench to the bedside. The BRCA1 gene is only one example of how decades of research established how errors in this gene increase cancer risk. The association of another important gene named PTEN with increased cancer risk has also been well established. Harmful germline mutations in PTEN increase the risk of thyroid cancer by 72-fold, elevate the lifetime risks of breast (85%), endometrial (28%), and kidney (33%) cancers, and increase the risk of developing a second cancer by 7-fold, all as compared to the US general population. Practically, this translates to: when a patient undergoes genetic testing and a harmful inherited PTEN mutation is uncovered, PTEN-driven clinical management ensues. For example, breast cancer screening starts as early as age 30 due to an increased 85% lifetime risk compared to just 12% in the US general population.

Is it really that simple?

The answer is yes and no. Simplistically, it is yes when a gene is known and years of research show clear associations with cancer (for example PTEN and BRCA1). However, the reality is that hundreds of thousands of individuals with cancer have errors in unknown and yet-to-be identified genes. Therefore, in the absence of knowledge regarding the functions of these genes and epidemiological studies to estimate how likely they are to cause cancer, we can neither (fully) preempt the risk nor know the best course of clinical action. And this is precisely why we do research.

As a translational cancer genetics researcher-in-training, I am constantly challenged and equally inspired by the idea of how the work we do at the bench contributes to the promotion of health and understanding the causes of complex diseases such as cancer. I specifically study thyroid cancer, the most common cancer of the endocrine glands, and the fastest rising cancer in women and second fastest rising in men in the US. Our gene-hunting journey started by examining a multi-generational family with thyroid cancer in multiple members and occurring at a much younger age than expected (the youngest affected member was 21 years old). We found that all affected family members had a harmful inherited mutation in a gene named SEC23B. The mutation was not found in any unaffected family members. SEC23B encodes for a protein involved in the transport of all proteins within cells.

While this was not the first time our team has discovered novel cancer-causing mutations, what was truly remarkable is that the SEC23B gene had been identified back in 2009 as the cause of a very rare type of anemia, but not cancer. In anemia, genetic errors in the SEC23B gene lead to decreased expression or loss of function of the SEC23B protein. In contrast to anemia, we discovered that genetic errors seen in a cancer context result in change-of-function of SEC23B (rather than loss of function). Normal thyroid cells expressing such mutated SEC23B grew faster, formed larger cell colonies, invaded more aggressively, and were able to survive in a very stressful microenvironment—all major hallmarks of cancer. So with the discovery of novel cancer-causing genes, the challenge is that unlike PTEN and BRCA1 where years of empowering knowledge translates into effective course of clinical action, for SEC23B we are indeed surfing an unfamiliar shore with exciting opportunities to help explain how and why it causes cancer – and why thyroid cancer specifically?

In the end, it may sound scary for one to know they have a genetic error that can lead to elevated risk for cancer, but this same knowledge is empowering to preemptively implement preventive or treatment strategies. The mission is to truly use such knowledge to improve human health and quality of life, and hence promote the medical “nirvana” of graceful aging. Scientists and physicians are merely detectives at heart. Solving the mysteries of the genetic code is an anticipated eureka moment.

Lamis Yehia is a 2011 fellow of the Fulbright Science & Technology Award program from Lebanon. Lamis is a doctoral candidate at the Cleveland Clinic’s Genomic Medicine Institute and the Department of Pathology, Case Western Reserve University, in Cleveland.

The March edition of TGS magazine was guest edited by Gwynne Lim, a 2010 fellow of the Fulbright Science & Technology Award, from Singapore.